Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Diabetes reversal by inhibition of the low-molecular-weight tyrosine phosphatase


Obesity-associated insulin resistance plays a central role in type 2 diabetes. As such, tyrosine phosphatases that dephosphorylate the insulin receptor (IR) are potential therapeutic targets. The low-molecular-weight protein tyrosine phosphatase (LMPTP) is a proposed IR phosphatase, yet its role in insulin signaling in vivo has not been defined. Here we show that global and liver-specific LMPTP deletion protects mice from high-fat diet-induced diabetes without affecting body weight. To examine the role of the catalytic activity of LMPTP, we developed a small-molecule inhibitor with a novel uncompetitive mechanism, a unique binding site at the opening of the catalytic pocket, and an exquisite selectivity over other phosphatases. This inhibitor is orally bioavailable, and it increases liver IR phosphorylation in vivo and reverses high-fat diet-induced diabetes. Our findings suggest that LMPTP is a key promoter of insulin resistance and that LMPTP inhibitors would be beneficial for treating type 2 diabetes.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Genetic deletion of LMPTP improves glucose tolerance of obese mice and increases liver insulin receptor signaling.
Figure 2: High-throughput screen of NIH chemical library identifies selective inhibitors of LMPTP.
Figure 3: The LMPTP inhibitor series is selective and displays an uncompetitive mechanism of action.
Figure 4: Structural determinants of LMPTP inhibition.
Figure 5: Compound 23 increases liver cell insulin signaling, is orally bioavailable and reverses diabetes in obese mice.

Accession codes

Primary accessions

Protein Data Bank

Referenced accessions


Protein Data Bank


  1. 1

    Biddinger, S.B. & Kahn, C.R. From mice to men: insights into the insulin resistance syndromes. Annu. Rev. Physiol. 68, 123–158 (2006).

    CAS  Article  Google Scholar 

  2. 2

    Kahn, S.E., Hull, R.L. & Utzschneider, K.M. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444, 840–846 (2006).

    CAS  Article  Google Scholar 

  3. 3

    Saltiel, A.R. & Kahn, C.R. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414, 799–806 (2001).

    CAS  Article  Google Scholar 

  4. 4

    White, M.F., Shoelson, S.E., Keutmann, H. & Kahn, C.R. A cascade of tyrosine autophosphorylation in the beta-subunit activates the phosphotransferase of the insulin receptor. J. Biol. Chem. 263, 2969–2980 (1988).

    CAS  PubMed  Google Scholar 

  5. 5

    Musi, N. & Goodyear, L.J. Insulin resistance and improvements in signal transduction. Endocrine 29, 73–80 (2006).

    CAS  Article  Google Scholar 

  6. 6

    Alonso, A. et al. Protein tyrosine phosphatases in the human genome. Cell 117, 699–711 (2004).

    CAS  Article  Google Scholar 

  7. 7

    Elchebly, M. et al. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 283, 1544–1548 (1999).

    CAS  Article  Google Scholar 

  8. 8

    Kasibhatla, B., Wos, J. & Peters, K.G. Targeting protein tyrosine phosphatase to enhance insulin action for the potential treatment of diabetes. Curr. Opin. Investig. Drugs 8, 805–813 (2007).

    CAS  PubMed  Google Scholar 

  9. 9

    Chiarugi, P. et al. LMW-PTP is a negative regulator of insulin-mediated mitotic and metabolic signalling. Biochem. Biophys. Res. Commun. 238, 676–682 (1997).

    CAS  Article  Google Scholar 

  10. 10

    Bottini, N., MacMurray, J., Peters, W., Rostamkhani, M. & Comings, D.E. Association of the acid phosphatase (ACP1) gene with triglyceride levels in obese women. Mol. Genet. Metab. 77, 226–229 (2002).

    CAS  Article  Google Scholar 

  11. 11

    Gloria-Bottini, F. et al. Phosphotyrosine protein phosphatases and diabetic pregnancy: an association between low molecular weight acid phosphatase and degree of glycemic control. Experientia 52, 340–343 (1996).

    CAS  Article  Google Scholar 

  12. 12

    Lucarini, N. et al. Phosphotyrosine-protein-phosphatase and diabetic disorders. Further studies on the relationship between low molecular weight acid phosphatase genotype and degree of glycemic control. Dis. Markers 14, 121–125 (1998).

    CAS  Article  Google Scholar 

  13. 13

    Iannaccone, U. et al. Serum glucose concentration and ACP1 genotype in healthy adult subjects. Metabolism 54, 891–894 (2005).

    CAS  Article  Google Scholar 

  14. 14

    Pandey, S.K. et al. Reduction of low molecular weight protein-tyrosine phosphatase expression improves hyperglycemia and insulin sensitivity in obese mice. J. Biol. Chem. 282, 14291–14299 (2007).

    CAS  Article  Google Scholar 

  15. 15

    Stefani, M. et al. Dephosphorylation of tyrosine phosphorylated synthetic peptides by rat liver phosphotyrosine protein phosphatase isoenzymes. FEBS Lett. 326, 131–134 (1993).

    CAS  Article  Google Scholar 

  16. 16

    Barr, A.J. Protein tyrosine phosphatases as drug targets: strategies and challenges of inhibitor development. Future Med. Chem. 2, 1563–1576 (2010).

    CAS  Article  Google Scholar 

  17. 17

    Maccari, R. & Ottanà, R. Low molecular weight phosphotyrosine protein phosphatases as emerging targets for the design of novel therapeutic agents. J. Med. Chem. 55, 2–22 (2012).

    CAS  Article  Google Scholar 

  18. 18

    Ottanà, R. et al. 5-Arylidene-2-phenylimino-4-thiazolidinones as PTP1B and LMW-PTP inhibitors. Bioorg. Med. Chem. 17, 1928–1937 (2009).

    Article  Google Scholar 

  19. 19

    Maccari, R. et al. Structure-based optimization of benzoic acids as inhibitors of protein tyrosine phosphatase 1B and low molecular weight protein tyrosine phosphatase. Chem. Med. Chem. 4, 957–962 (2009).

    CAS  Article  Google Scholar 

  20. 20

    Maccari, R. et al. 5-Arylidene-2,4-thiazolidinediones as inhibitors of protein tyrosine phosphatases. Bioorg. Med. Chem. 15, 5137–5149 (2007).

    CAS  Article  Google Scholar 

  21. 21

    Ottanà, R. et al. Synthesis, biological activity and structure-activity relationships of new benzoic acid-based protein tyrosine phosphatase inhibitors endowed with insulinomimetic effects in mouse C2C12 skeletal muscle cells. Eur. J. Med. Chem. 71, 112–127 (2014).

    Article  Google Scholar 

  22. 22

    Forghieri, M. et al. Synthesis, activity and molecular modeling of a new series of chromones as low molecular weight protein tyrosine phosphatase inhibitors. Bioorg. Med. Chem. 17, 2658–2672 (2009).

    CAS  Article  Google Scholar 

  23. 23

    Wade, F. et al. Deletion of low molecular weight protein tyrosine phosphatase (Acp1) protects against stress-induced cardiomyopathy. J. Pathol. 237, 482–494 (2015).

    CAS  Article  Google Scholar 

  24. 24

    Surwit, R.S., Kuhn, C.M., Cochrane, C., McCubbin, J.A. & Feinglos, M.N. Diet-induced type II diabetes in C57BL/6J mice. Diabetes 37, 1163–1167 (1988).

    CAS  Article  Google Scholar 

  25. 25

    McGovern, S.L., Helfand, B.T., Feng, B. & Shoichet, B.K. A specific mechanism of nonspecific inhibition. J. Med. Chem. 46, 4265–4272 (2003).

    CAS  Article  Google Scholar 

  26. 26

    Baell, J.B. & Holloway, G.A. New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J. Med. Chem. 53, 2719–2740 (2010).

    CAS  Article  Google Scholar 

  27. 27

    Ardecky, R.J. et al. in Probe Reports from the NIH Molecular Libraries Program (National Center for Biotechnology Information, 2010).

  28. 28

    Ramponi, G. & Stefani, M. Structure and function of the low Mr phosphotyrosine protein phosphatases. Biochim. Biophys. Acta 1341, 137–156 (1997).

    CAS  Article  Google Scholar 

  29. 29

    Zhang, M., Zhou, M., Van Etten, R.L. & Stauffacher, C.V. Crystal structure of bovine low molecular weight phosphotyrosyl phosphatase complexed with the transition state analog vanadate. Biochemistry 36, 15–23 (1997).

    CAS  Article  Google Scholar 

  30. 30

    Rastogi, V.K. et al. 1H, 15N, and 13C resonance assignments of low molecular weight human cytoplasmic protein tyrosine phosphatase-A (HCPTP-A). J. Biomol. NMR 23, 251–252 (2002).

    CAS  Article  Google Scholar 

  31. 31

    Su, X.D., Taddei, N., Stefani, M., Ramponi, G. & Nordlund, P. The crystal structure of a low-molecular-weight phosphotyrosine protein phosphatase. Nature 370, 575–578 (1994).

    CAS  Article  Google Scholar 

  32. 32

    Brandão, T.A., Hengge, A.C. & Johnson, S.J. Insights into the reaction of protein-tyrosine phosphatase 1B: crystal structures for transition state analogs of both catalytic steps. J. Biol. Chem. 285, 15874–15883 (2010).

    Article  Google Scholar 

  33. 33

    Pannifer, A.D., Flint, A.J., Tonks, N.K. & Barford, D. Visualization of the cysteinyl-phosphate intermediate of a protein-tyrosine phosphatase by x-ray crystallography. J. Biol. Chem. 273, 10454–10462 (1998).

    CAS  Article  Google Scholar 

  34. 34

    Kiselar, J.G., Maleknia, S.D., Sullivan, M., Downard, K.M. & Chance, M.R. Hydroxyl radical probe of protein surfaces using synchrotron X-ray radiolysis and mass spectrometry. Int. J. Radiat. Biol. 78, 101–114 (2002).

    CAS  Article  Google Scholar 

  35. 35

    Xu, G. & Chance, M.R. Hydroxyl radical-mediated modification of proteins as probes for structural proteomics. Chem. Rev. 107, 3514–3543 (2007).

    CAS  Article  Google Scholar 

  36. 36

    Logan, T.M. et al. Solution structure of a low molecular weight protein tyrosine phosphatase. Biochemistry 33, 11087–11096 (1994).

    CAS  Article  Google Scholar 

  37. 37

    Chiarugi, P. et al. LMW-PTP is a positive regulator of tumor onset and growth. Oncogene 23, 3905–3914 (2004).

    CAS  Article  Google Scholar 

  38. 38

    Liu, P., Jenkins, N.A. & Copeland, N.G. A highly efficient recombineering-based method for generating conditional knockout mutations. Genome Res. 13, 476–484 (2003).

    CAS  Article  Google Scholar 

  39. 39

    Wu, S. et al. Multidentate small-molecule inhibitors of vaccinia H1-related (VHR) phosphatase decrease proliferation of cervix cancer cells. J. Med. Chem. 52, 6716–6723 (2009).

    CAS  Article  Google Scholar 

  40. 40

    Wu, S., Bottini, M., Rickert, R.C., Mustelin, T. & Tautz, L. In silico screening for PTPN22 inhibitors: active hits from an inactive phosphatase conformation. ChemMedChem 4, 440–444 (2009).

    CAS  Article  Google Scholar 

  41. 41

    Kholod, N. & Mustelin, T. Novel vectors for co-expression of two proteins in E. coli. Biotechniques 31, 322–323, 326–328 (2001).

    CAS  Article  Google Scholar 

  42. 42

    Stanford, S.M. et al. Discovery of a novel series of inhibitors of lymphoid tyrosine phosphatase with activity in human T cells. J. Med. Chem. 54, 1640–1654 (2011).

    CAS  Article  Google Scholar 

  43. 43

    Mustelin, T., Tautz, L. & Page, R. Structure of the hematopoietic tyrosine phosphatase (HePTP) catalytic domain: structure of a KIM phosphatase with phosphate bound at the active site. J. Mol. Biol. 354, 150–163 (2005).

    CAS  Article  Google Scholar 

  44. 44

    Kabsch, W. Xds. Acta Crystallogr. D Biol. Crystallogr. 66, 125–132 (2010).

    CAS  Article  Google Scholar 

  45. 45

    Collaborative Computational Project, Number 4. The CCP4 suite: programs for protein crystallography. Acta Crystallogr. D Biol. Crystallogr. 50, 760–763 (1994).

  46. 46

    McCoy, A.J. et al. Phaser crystallographic software. J. Appl. Crystallogr. 40, 658–674 (2007).

    CAS  Article  Google Scholar 

  47. 47

    Murshudov, G.N., Vagin, A.A. & Dodson, E.J. Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallor. D Biol. Crystallogr. 53, 240–255 (1997).

    CAS  Article  Google Scholar 

  48. 48

    Emsley, P. & Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr. D Biol. Crystallogr. 60, 2126–2132 (2004).

    Article  Google Scholar 

  49. 49

    Adams, P.D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D Biol. Crystallogr. 66, 213–221 (2010).

    CAS  Article  Google Scholar 

  50. 50

    Gupta, S., Sullivan, M., Toomey, J., Kiselar, J. & Chance, M.R. The Beamline X28C of the Center for Synchrotron Biosciences: a national resource for biomolecular structure and dynamics experiments using synchrotron footprinting. J. Synchrotron Radiat. 14, 233–243 (2007).

    CAS  Article  Google Scholar 

  51. 51

    Xu, G. & Chance, M.R. Radiolytic modification and reactivity of amino acid residues serving as structural probes for protein footprinting. Anal. Chem. 77, 4549–4555 (2005).

    CAS  Article  Google Scholar 

  52. 52

    Xu, G., Kiselar, J., He, Q. & Chance, M.R. Secondary reactions and strategies to improve quantitative protein footprinting. Anal. Chem. 77, 3029–3037 (2005).

    CAS  Article  Google Scholar 

  53. 53

    Xu, H. & Freitas, M.A. A mass accuracy sensitive probability based scoring algorithm for database searching of tandem mass spectrometry data. BMC Bioinformatics 8, 133 (2007).

    Article  Google Scholar 

  54. 54

    Takamoto, K. & Chance, M.R. Radiolytic protein footprinting with mass spectrometry to probe the structure of macromolecular complexes. Annu. Rev. Biophys. Biomol. Struct. 35, 251–276 (2006).

    CAS  Article  Google Scholar 

Download references


The authors are grateful to L. Tautz at the Sanford Burnham Prebys Medical Discovery Institute for providing recombinant VHR and LYP proteins, to E. Santelli for critical review of the manuscript, to the University of California Davis Mouse Biology Program for help with image preparation, to S. Gupta for assistance with sample irradiation at the Advanced Light Source of Lawrence Berkeley National Laboratory, and to Z. Mikulski and A. Lamberth for help with histological analysis at the Histology and Microscopy Core at the La Jolla Institute for Allergy and Immunology. This work was supported by grants R03DA033986 (to N.B.) and R01DK106233 from the National Institutes of Health (to N.B. and A.B.P.). S.M.S. was supported by the American Diabetes Association Pathway to Stop Diabetes Grant 1-15-INI-13 and by the University of California San Diego Diabetes Research Center grant P30DK063491 from the National Institutes of Health. The X-ray footprinting was carried out by S. Gupta at beamline 3.2.1 of the Advanced Light Source of Lawrence Berkeley National Laboratory, which is supported by the Director, Office of Science, Office of Basic Energy Sciences, of the US Department of Energy under Contract No. DE-AC02-05CH11231. This is manuscript #1882 from the La Jolla Institute for Allergy and Immunology.

Author information




S.M.S., A.E.A., T.D.Y.C., T.M., S.S., L.A.B., R.C.L., A.B.P. and N.B. participated in study conception and design. S.M.S., V.Z., M.R.B., Y.L., A.B. and S.S. performed in vivo experiments. S.M.S., V.Z. and M.R.B. performed cell biology experiments. S.M.S., V.Z., M.P.H., M.R.B., F.Y. and S.K. performed in vitro enzymatic assays. R.J.A., J.Z., S.R.G. and A.B.P. designed chemical compounds and/or performed chemical syntheses. R.J.A. and A.B.P. coordinated compound stability and PK studies. A.E.A., M.P.H., M.R.B., A.A.B., Y.L., G.W.C. and L.A.B. produced recombinant proteins. A.A.B. performed ITC experiments. A.E.A., G.W.C., J.Y. and L.A.B. performed NMR and X-ray crystallography experiments. J.K. performed hydroxyl radical footprinting experiments. S.M.S., A.E.A., V.Z., R.J.A., M.P.H., J.Z., S.R.G., M.R.B., F.Y., A.A.B., J.K., Y.L., G.W.C., S.K., J.Y., A.B., T.D.Y.C., T.M., S.S., L.A.B., R.C.L., A.B.P. and N.B. analyzed and interpreted data. S.M.S., R.C.L., A.B.P. and N.B. wrote the manuscript.

Corresponding author

Correspondence to Nunzio Bottini.

Ethics declarations

Competing interests

The La Jolla Institute for Allergy and Immunology and Sanford Burnham Medical Discovery Institute hold a pending patent, WO 2016/061280 A1, “Inhibitors of low molecular weight protein tyrosine phosphatase and uses thereof,” with N.B., J.Z., S.R.G., S.M.S., A.B.P., T.D.Y.C., M.P.H. and R.J.A. named as inventors.

Supplementary information

Source data

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Stanford, S., Aleshin, A., Zhang, V. et al. Diabetes reversal by inhibition of the low-molecular-weight tyrosine phosphatase. Nat Chem Biol 13, 624–632 (2017).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing